In its 13th annual report, “Piecing Together the HIV Prevention Puzzle,” the AIDS Vaccine Advocacy Coalition (AVAC) says there is an “energized focus on discovery, innovation and basic science” in the field of AIDS vaccines, but noted that successful HIV prevention will likely depend on a combination of approaches and strategies.

Casting comprehensive HIV prevention as a puzzle still missing vital pieces, AVAC lists eight recommendations in its report. The recommendations include development of better communication tools to explain upcoming vaccine trials to a lay audience, as well as to communicate the result of the soon-to-be-completed Phase III prime-boost trial in Thailand. Another focus of the report is the role of the Global HIV Vaccine Enterprise, an international alliance of researchers, funders, and advocates committed to accelerating the development of an AIDS vaccine. Based on interviews with various stakeholders, AVAC concluded that the “added value” of the Enterprise is “not yet completely convincing.” The AVAC Report recommends that the Enterprise should demonstrate greater leadership, particularly through publication of an updated scientific plan in 2010.

AVAC also highlighted advances in the field—more initiatives aimed at bringing young investigators into HIV prevention research was a notable area of progress. And with the initial results from the now infamous STEP trial nearly two years old, AVAC noted that the failure of Merck’s vaccine candidate has helped propel new and exciting directions in research.

AVAC, which was formed in 1995, uses public education and policy analysis to advocate for the development of an AIDS vaccine. The organization has also taken a central role in advocating for other HIV prevention strategies, primarily pre-exposure prophylaxis (PrEP)—the delivery of antiretrovirals to uninfected individuals to prevent HIV infection. The report, written by AVAC staff, urged the HIV prevention field to prepare for the potential efficacy of prevention strategies such as PrEP, and said governments in the countries hardest hit by HIV needed to “add specificity” around financial, infrastructure, and other implications regarding the possible use of this modality in the future.

AVAC dedicated its report to AIDS activists Martin Delaney, who helped found the San Francisco-based AIDS service organization Project Inform, and Lynde Francis, one of the first HIV-infected individuals to disclose her status in Zimbabwe and the founder of The Centre for AIDS Services in that country. Both died this year.

The University of KwaZulu-Natal (UKZN) in South Africa, which claims the highest AIDS prevalence in the world, has teamed up with the Howard Hughes Medical Institute (HHMI) in Maryland to develop a research center focused on the twin scourges of tuberculosis (TB) and HIV. When HIV and TB infections coexist, it often comes with dire consequences—TB is the leading killer of people with HIV/AIDS, according to Joint United Nations Programme on HIV/AIDS (UNAIDS).

The KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) will receive US$60 million over 10 years from HHMI—$20 million to establish K-RITH and $4 million a year for 10 years to support research projects. The UKZN is committing about $11 million for infrastructure costs. The new institute will be housed within the Nelson Mandela School of Medicine in Durban. K-RITH will also be adjoined to the Doris Duke Medical Research Institute, which houses several AIDS research groups, including the Human Pathogenesis Programme headed by Bruce Walker, an HHMI investigator, and the Center for the AIDS Programme of Research in South Africa, led by Salim Abdool Karim.

K-RITH will initially focus on four research areas: the development of rapid and more effective diagnostic tests for TB; characterizing drug-resistant strains of TB; analyzing immune responses to TB, particularly those seen in people also infected with HIV; and the study of recurrent TB infections in HIV-infected individuals. K-RITH will also be involved in testing candidate vaccines, both for TB and HIV, and researchers hope the new institute will become a magnet for young African scientists who want to base their laboratory work there but are hindered by the lack of research facilities and funding.

What are the methods used to ensure that data from AIDS vaccine trials are of high quality?

AIDS vaccine clinical trials depend upon a number of factors to be successful. The candidates undergoing testing must first submit to extensive pre-clinical evaluationÑinitially in the laboratory and later in animal modelsÑso researchers and regulators, who approve the clinical studies, can obtain essential information about whether the vaccine candidates are safe, and whether they demonstrate efficacy in animals. This can help predict how well they might work in people (see VAX October 2006 Primer on Understanding AIDS Vaccine Pre-Clinical Development).

AIDS vaccine trials must also follow Good Clinical Practice (GCP) guidelines, which are an international quality standard for conduct of clinical trials. Ethical and regulatory review committees from the countries and institutions that are involved in the clinical trial must provide approval for the trial before it can begin, and also provide guidelines for the trial staff (see VAX June 2005 Primer on Understanding Informed Consent).

In addition, external committees known as Data and Safety Monitoring Boards (DSMBs) or Safety Review Boards (SRBs), monitor the trial once it is underway (see VAX June 2007 Primer on Understanding Data Safety Monitoring Boards). The DSMB or SRB for a clinical trial evaluates the data regarding safety and efficacy that emerges from the trial while it is in process.

Collecting quality data is central to the mission and purpose of a clinical trial. Without consistent and unambiguous methods of data collection, researchers run the risk of conducting a trial that is unable to draw any firm conclusions about side effects, adverse events, or even whether the vaccine candidate is effective or not. Therefore, clinical trial sites continually work to make sure the process of data collection is as accurate as possible. Also, since many clinical trials are conducted at multiple centers, often in different countries and regions of the world, it is necessary for all data to be recorded consistently, so that it is comparable.

Data entry

Collecting high-quality data starts with training the staff to properly collect and record information, both by hand and electronically. Usually, nurses, physicians, and counselors working on a clinical trial collect data from volunteers. During the screening process for a trial, nurses will conduct physical exams, HIV tests, and other baseline medical criteria from potential volunteers so there is a record of their general health before they are enrolled in the trial. Then, throughout the course of the trial, nurses, physicians, and counselors will collect additional data from all of the volunteers such as measuring and recording a volunteer’s vital signsÑgenerally their temperature, blood pressure, pulse, and respiratory rate.

Once volunteers in the trial have received vaccinations with either the vaccine candidate or placebo, nurses or physicians also examine volunteers for any potential adverse events, including fever, rash, or headaches. Periodic testing for HIV is also performed and all volunteers receive counseling about how to reduce their risk of HIV infection. The frequency at which this data is collected is defined in the trial protocol, which describes the objectives, design, methodology, and statistical considerations for the study. It is essential that all clinical research centers participating in a trial record data in consistent intervals of time.

These observations are all carefully recorded on what is known as a source documentÑa paper record kept for each volunteer with the observations made by the nurse, physician, or counselor.

Along with the source documents, staff at the vaccine research centers record data on electronic case report forms, which are transmitted to a data coordinating center for analysis by statisticians. It is important to use a common case report form so that all data is collected in exactly the same manner for each volunteer, and to ensure that the same standards are used to evaluate any possible adverse event. For instance, if clinical trial centers have different guidelines for what constitutes moderate or severe redness on the arm following inoculation, it may be difficult to conclude how to characterize the severity of this reaction at the conclusion of the trial. Although such observations are still subject to some level of human interpretation, clinical trial specialists try to control this as much as possible by creating standardized tools.

They also have built a series of checks and balances into the case report forms, which can help identify erroneous entriesÑsuch as an unusually high blood pressure of a trial volunteerÑand alert researchers to take a closer look. Additionally, the sponsors of a trial have monitors who compare the data on the source document with information on the case report forms to make sure the information is consistent.

Standardized case report forms become particularly important in large, Phase III trials where there are several thousand volunteers and hence drastically more data to analyze and compare. Since these large trials are also the final step of clinical evaluation prior to the candidate being considered for regulatory approval, it is essential that data regarding any adverse events or the efficacy of the candidate is recorded accurately and consistently since this information will influence regulatory considerations regarding licensure of the vaccine candidate for public use.